This laboratory is devoted to the study of the human keratinocyte; its multiplication, its terminal differentiation, and its specific gene expression. The keratinocyte is a unique example of a terminally differentiating cell type with high susceptibility to neoplastic change. Because the cell type is now so efficiently cultivable and exhibits many differentiated properties in culture, most of the work uses cell cultures. However, the cultures are readily transplantable to athymic animals where they generate normal human epidermis. This is a very sensitive test for normal keratinocytes; transformation of the cultured cells with a viral oncogene results in very evident perturbation of the differentiated structure of the grafted epithelium. There is no other tissue which can be easily generated from cultured cells and studied this way. Much of the work will be focused on regulated gene expression, using involucrin and other specialized proteins of terminal differentiation. In this work, study of transfected genes and their resulting expression in small (proliferating) and large (terminally differentiating) cells, separated by elutriation, has already shown that genes are expressed with tissue and cell compartment specificity. Changes in gene expression after grafting of cultured cells will be studied. The signals that turn on gene expression in large cells must be closely related to those that arrest proliferation, since altered gene expression is basic to the development of neoplasia.